Sulfur-containing thyroxane derivatives and their use as hair growth promotors

ABSTRACT

The present disclosure describes novel compounds of formula (A), wherein R1-R12, X and Y have the meanings given in the specification and compositions containing them which are particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The compounds described herein are cardiac-sparing.

This application claims the benefit of provisional application No.60/137/063, filed Jun. 1, 1994.

FIELD OF THE INVENTION

The present invention relates to methods for treating hair loss isarresting and/or reversing hair loss and promoting hair growth.

BACKGROUND OF THE INVENTION

Hair loss is a common problem which occurs, for example, through naturalprocesses or is often chemically promoted through the use of certaintherapeutic drugs designed to alleviate conditions such as cancer. Oftensuch hair loss is accompanied by lack of hair regrowth which causespartial or full baldness.

As is well-known in the art, hair growth occurs by a cycle of activitywhich involves alternating periods of growth and rest. This cycle isoften divided into three main stages which are known as anagen, catagen,and telogen. Anagen is the growth phase of the cycle and may becharacterized by penetration of the hair follicle deep into the dermiswith rapid proliferation of cells which are differentiating to formhair. The next phase is catagen, which is a transitional stage marked bythe cessation of cell division, and during which the hair follicleregresses through the dermis and hair growth is ceased. The next phase,telogen, is often characterized as the resting stage during which theregressed follicle contains a germ with tightly packed dermal papillacells. At telogen, the initiation of a new anagen phase is caused byrapid cell proliferation in the germ, expansion of the dermal papilla,and elaboration of basement membrane components. Wherein hair growthceases, most of the hair follicles reside in telogen and anagen is notengaged, thus causing the onset of full or partial baldness.

There have been many attempts in the literature to invoke the regrowthof hair by, for example, the promotion or prolongation of anagen.Currently, there are two drugs approved by the United States Food andDrug Administration for the treatment of male pattern baldness: topicalminoxidil (marketed as Rogaine® by Pharmacia & Upjohn), and oralfinasteride (marketed as Propecia® by Merck & Co., Inc.). For severalreasons, however, including safety concerns and/or lack of efficacy, thesearch for efficacious hair growth inducers is ongoing.

Interestingly, it is known that the thyroid hormone known as thyroxine(“T4”) converts to thyronine (“T3”) in human skin by deiodinase 1, aselenoprotein. Selenium deficiency causes a decrease in T3 levels due toa decrease in deiodinase I activity; this reduction in T3 levels isstrongly associated with hair loss. Consistent with this observation,hair growth is a reported side effect of administration of T4. See,e.g., Berman. “Peripheral Effects of L-Thyroxine on Hair Growth andColoration in Cattle ”. Journal of Endocrinology, Vol. 20, pp. 282-292(1960): and Gunaratnam. “The Effects of Thyroxine on Hair Growth in theDog”, J. Small Anim. Pract., Vol. 27, pp. 17-29 (1986). Furthermore, T3and T4 have been the subject of several patent publications relating totreatment of hair loss. See, e.g., Fischer et al., DE 1,617,477,published Jan. 8, 1970; Mortimer, GB 2,138,286, published Oct. 24, 1984;and Lindenbaum, WO 96/25943, assigned to Life Medical Sciences. Inc.,published Aug. 29, 1996.

Unfortunately, however, administration of T3 and/or T4 to treat hairloss is not practicable because these thyroid hormones are also known toinduce significant cardiotoxicity. See, e.g., Walker et al., U.S. Pat.No. 5,284,971, assigned to Syntex, issued Feb. 8, 1994 and Emmett etal., U.S. Pat. No. 5,061,798, assigned to Smith Kline & FrenchLaboratories, issued Oct. 29, 1991. Surprisingly, the present inventorshave discovered compounds which strongly initiate hair growth withoutinducing cardiotoxicity. Consistent with this discovery, but withoutintending to be limited by theory, the present inventors havesurprisingly discovered that the preferred compounds of the presentinvention interact strongly with hair-selective thyroid hormonereceptors but interact less strongly, or not at all, withheart-selective hormone receptors. These unique properties are, ofcourse, not shared with T3 and/or T4. Accordingly, the compounds andcompositions herein are useful for treating hair loss, includingarresting and/or reversing hair loss and promoting hair growth.

SUMMARY OF THE INVENTION

The present invention relates to compounds and compositions which areparticularly useful for treating hair loss in mammals, includingarresting and/or reversing hair loss and promoting hair growth.

The compounds of the present invention have the structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzableamides, esters, and imides thereof, wherein R₁, R₂, R₃, R₄, R₅, R₆, R₆′,R₇, R₈, R₉, R₁₀, Y, X, R₁₁, and R₁₂ are defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The present, invention relates to compounds and compositions which areparticularly useful for treating hair loss in mammals, includingarresting and/or reversing hair loss and promoting hair growth.

In addition to discovering that the present compounds are useful fortreating hair loss, the present inventors have also surprisinglydiscovered that the preferred compounds of the present invention arecardiac-sparing.

Publications and patents are referred to throughout this disclosure. Allreferences cited herein are hereby incorporated by reference.

All percentages, ratios, and proportions used herein are by weightunless otherwise specified.

In the description of the invention various embodiments and/orindividual features are disclosed. As will be apparent to the ordinarilyskilled practitioner all combinations of such embodiments and featuresare possible and can result in preferred executions of the invention.

As used herein, wherein any variable, moiety, group, or the like occursmore than one time in any variable or structure, its definition at eachoccurrence is independent of its definition at every other occurrence.

Definition and Usage of Terms

The following is a list of definitions for terms used herein:

As used herein “salt” is a cationic salt formed at any acidic (e.g.,carboxyl) group, or an anionic salt formed at any basic (e.g., amino)group. Many such salts are known in the art. Preferred cationic saltsinclude the alkali metal salts (such as, for example, sodium andpotassium), alkaline earth metal salts (such as, for example, magnesiumand calcium), and organic salts. Preferred anionic salts include thehalides (such as, for example, chloride salts). Such acceptable saltsmust, when administered, be appropriate for mammalian use.

As used herein, “alkenyl” is an unsubstituted or substituted hydrocarbonchain radical having from 2 to about 15 carbon atoms; preferably from 2to about 10 carbon atoms; more preferably from 2 to about 8 carbonatoms, and most preferably from about 2 to about 6 carbon atoms.Alkenyls have at least one olefinic double bond. Non-limiting examplesof alkenyls include vinyl, allyl, and butenyl.

As used herein, “alkoxy” is an oxygen radical having an alkyl, alkenyl,or alkynyl, preferably an alkyl or alkenyl, and most preferably an alkylsubstituent. Examples of alkoxy radicals include —O-alkyl and—O-alkenyl. An alkoxy radical may be substituted or unsubstituted.

As used herein, “aryloxy” is an oxygen radical having an arylsubstituent. An aryloxy radical may be substituted or unsubstituted.

As used herein, “alkyl” is an unsubstituted or substituted saturatedhydrocarbon chain radical having from 1 to about 15 carbon atoms;preferably from 1 to about 10 carbon atoms: more preferably from 1 toabout 6 carbon atoms; and most preferably from 1 to about 4 carbonatoms. Preferred alkyls include, for example, methyl, ethyl, propyl,iso-propyl, and butyl.

As used herein, “alkylene” refers to an alkyl, alkenyl, or alkynyl whichis a diradical. For example, “methylene” is —CH₂—. Alkylenes may besubstituted or unsubstituted.

As used herein, “alkynyl” is an unsubstituted or substituted hydrocarbonchain radical having from 2 to about 15 carbon atoms; preferably from 2to about 10 carbon atoms; more preferably from 2 to about 8 carbonatoms, and most preferably from about 2 to about 6 carbon atoms.Alkynyls have at least one triple bond.

As used herein, “aryl” is an aromatic ring radical which is eithercarbocyclic or heterocyclic. Preferred aryl groups include, for example,phenyl, benzyl, tolyl, xylyl, cumenyl, napthyl, biphenyl, thienyl,furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl,quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl,indenyl, azulenyl, fluorenyl, anthracenyl, oxazolyl, isoxazolyl,isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, indolizinyl, indolyl,isoindolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, and the like. Aryls may be substituted or unsubstituted.

As used herein, “arylalkenyl” is an alkenyl radical substituted with anaryl group or an aryl radical substituted with an alkenyl group.Arylalkenyls may be substituted or unsubstituted.

As used herein, “arylalkyl” is an alkyl radical substituted with an arylgroup or an aryl radical substituted with an alkyl group. Preferredarylalkyl groups include benzyl, phenylethyl, and phenylpropyl.Arylalkyls may be substituted or unsubstituted.

As used herein, “biohydrolyzable amides” are amides of the compounds ofthe present invention which do not interfere with the activity of thecompound, or that are readily converted in vivo by a mammalian subjectto yield an active compound.

As used herein, “biohydrolyzable esters” are esters of the compounds ofthe present invention which do not interfere with the activity of thecompound, or that are readily converted in vivo by a mammalian subjectto yield an active compound.

As used herein, “biohydrolyzable imides” are imides of the compounds ofthe present invention which do not interfere with the activity of thecompound, or that are readily converted in vivo by a mammalian subjectto yield an active compound.

As used herein, “carbocyclic ring”, “carbocycle”, or the like is ahydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused,bridged, or spiro polycyclic rings. Unless otherwise specified,monocyclic rings contain from 3 to about 9 atoms, preferably from about4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycyclic ringscontain from about 7 to about 17 atoms, preferably from about 7 to about14 atoms, and most preferably 9 or 10 atoms. Carbocyclic rings(carbocycles) may be substituted or unsubstituted.

As used herein, “cycloalkyl” is a saturated carbocyclic or heterocyclicring radical. Preferred cycloalkyl groups include, for example,cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls may be substitutedor unsubstituted.

As used herein, “cycloalkenyl” is an unsaturated carbocyclic orheterocyclic ring radical having at least one double bond. Cycloalkenylsmay be substituted or unsubstituted.

As used herein, preferred “halogens” (or “halos” or the like) arebromine, chlorine, iodine, and fluorine, more preferably, bromine,chlorine, and iodine, even more preferably bromine and chlorine, andmost preferably chlorine.

As used herein, “heteroalkenyl” is an alkenyl radical comprised ofcarbon atoms and one or more heteroatoms wherein the heteroatoms areselected from the group consisting of oxygen, sulfur, nitrogen, andphosphorous, more preferably, oxygen, sulfur, and nitrogen.Heteroalkenyls may be substituted or unsubstituted.

As used herein, “heteroalkyl” is an alkyl radical comprised of carbonatoms and one or more heteroatoms wherein the heteroatoms are selectedfrom the croup consisting of oxygen, sulfur, nitrogen, and phosphorous,more preferably, oxygen, sulfur, and nitrogen. Heteroalkyls may besubstituted or unsubstituted.

As used herein, “heteroalkynyl” is an alkynyl radical comprised ofcarbon atoms and one or more heteroatoms wherein the heteroatoms areselected from the group consisting of oxygen, sulfur, nitrogen, andphosphorous, more preferably, oxygen, sulfur, and nitrogen.Heteroalkynyls may be substituted or unsubstituted.

As used herein, “heteroaryl” is an aryl radical comprised of carbonatoms and one or more heteroatoms wherein the heteroatoms are selectedfrom the group consisting of oxygen, sulfur, nitrogen, and phosphorous,more preferably, oxygen, sulfur, and nitrogen. Heteroaryls may besubstituted or unsubstituted.

As used herein, “heteroarylalkenyl” is an arylalkenyl radical whereinthe aryl group and/or the alkenyl group is comprised of carbon atoms andone or more heteroatoms wherein the heteroatoms are selected from thegroup consisting of oxygen, sulfur, nitrogen, and phosphorous, morepreferably, oxygen, sulfur, and nitrogen. Heteroarylalkenyls may besubstituted or unsubstituted.

As used herein, “heteroarylalkyl” is an arylalkyl radical wherein thearyl group and/or the alkyl group is comprised of carbon atoms and oneor more heteroatoms wherein the heteroatoms are selected from the groupconsisting of oxygen, sulfur, nitrogen, and phosphorous, morepreferably, oxygen, sulfur, and nitrogen. Heteroarylalkyls may besubstituted or unsubstituted.

As used herein, “heterocyclic ring”, “heterocycle”, or the like is aring radical comprised of carbon atoms and one or more heteroatoms inthe ring wherein the heteroatoms are selected from the group consistingof oxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen,sulfur, and nitrogen. Heterocycles are monocyclic or are fused, bridged,or Spiro polycyclic rings. Unless otherwise specified, monocyclescontain from 3 to about 9 atoms, preferably from about 4 to about 7atoms, and most preferably 5 or 6 atoms. Polycycles contain from about 7to about 17 atoms, preferably from about 7 to about 14 atoms, and mostpreferably 9 or 10 atoms. Heterocyclic rings (heterocycles) may besubstituted or unsubstituted.

As used herein, “heterocycloalkyl” is a cycloalkyl having at least oneheteroatom in the ring. Heterocycloalkyls may be substituted orunsubstituted.

As used herein, “heterocycloalkenyl” is a cycloalkenyl having at leastone heteroatom in the ring. Heterocycloalkyls may be substituted orunsubstituted.

As used herein, a “lower” moiety (e.g., “lower” alkyl) is moiety having1 to about 6, preferably 1 to about 4, carbon atoms.

As used herein, “pharmaceutically acceptable” means suitable for use ina human or other mammal.

As used herein, “safe and effective amount of a compound” (orcomposition, or the like) means an amount that is effective to exhibitbiological activity, preferably wherein the biological activity isarresting and/or reversing hair loss or promoting hair growth, at thesite(s) of activity in a mammalian subject, without undue adverse sideeffects (such as toxicity, irritation, or allergic response),commensurate with a reasonable benefit/risk ratio when used in themanner of this invention.

As used herein unless otherwise specified, the term “substituted” inreference to a group, moiety, or the like, means having one or moresubstituent groups each independently selected from hydrogen, alkyl,alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino, cyano, halo, thiol,aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl,morpholinyl, pyrrolidinyl), imino, hydroxyalkyl, aryloxy, and arylalkyl,preferably hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, amino,alkylamino, halo, thiol, and aryloxy, more preferably hydrogen, alkyl,alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino, and halo, even morepreferably hydrogen, alkyl, and alkoxy, and most preferably alkoxy.

Compounds of the Present Invention

The compounds of the present invention have the structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzableamides, esters, and imides thereof, wherein:

(a) R₁, R₂, R₅, R₇, and R₁₀ are each, independently, selected from thegroup consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, and heteroalkynyl;

(b) R₄ is selected from the group consisting of halogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl,heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, heteroarylalkyl, and heteroarylalkenyl: wherein when R₂ ishydrogen. Y is —CH₂CHK₁, X is selected from the group consisting of —NZ—and —NH—, and R₁₂ is C₁-C₄ alkyl, wherein K₁ is selected from hydrogenand C₁-C₄ alkyl and Z is C₁-C₄ alkyl, then R₄ is not arylalkyl;

(c) R₈ and R₉ are each, independently, selected from the groupconsisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl,heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,heteroarylalkyl, and heteroarylalkenyl, wherein at least one of R₈ andR₉ is not hydrogen;

(d) R₃ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl and heteroarylalkenyl;

(e) R₆ and R₆′ are each, independently, selected from the groupconsisting of nil and oxo;

(f) Y is selected from the group consisting of bond, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl;

(g) X is selected from the group consisting of —NZ—, —NH— and —O—;

(h) R₁₁ is selected from the group consisting of bond and —C(O)—;wherein when Y is bond and X is —O—, then R₁₁ is —C(O)—;

(i) R₁₂ is selected from the group consisting of alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, and heteroarylalkenyl; or wherein when R₁₁is bond, then R₁₂ and Z may be optionally bonded together to form acycle selected from the group consisting of cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl: wherein whenR₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl,then a heteroatom of R₁₂ is not directly covalently bonded to R₁₁;wherein when R₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl,heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, orheteroarylalkenyl, then a heteroatom of R₁₂ is not directly coalentlybonded to R₁₁; and wherein when R₁₁ is bond and X is —O—, then R₁₂ isnot methyl; and

(j) Z is selected from the group consisting of alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, and heteroalkynyl; or wherein when R₁₁ isbond, then R₁₂ and Z may be optionally bonded together to form a cycleselected from the group consisting of cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein whenR₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl,then a heteroatom of R₁₂ is not directly covalently bonded to R₁₁.

The present compounds are sulfur-bridged compounds linked through acarbon atom which is substituted with substituents R₆ and/or R₆′. Theremaining substituents, as well as R₆ and R₆′, are described in furtherdetail below.

The Substituents R₁, R₂, R₅, R₇, and R₁₀

The substituents R₁, R₂, R₅, R₇, and R₁₀ each substitute on one of thephenyl rings of the structure shown herein. R₁, R₂, R₅, R₇, and R₁₀ areeach, independently, selected from hydrogen, halogen, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl.

R₁, R₂, R₅, R₇, and R₁₀ are preferably each, independently, selectedfrom hydrogen, halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl,R₁, R₂, R₅, R₇, and R₁₀ are more preferably each, independently,selected from hydrogen, halogen, and lower alkyl. Most preferably, R₁,R₂, R₅, R₇, and R₁₀ are each hydrogen.

The Substituent R₄

The substituent R₄ is selected from halogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl,heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,heteroarylalkyl, and heteroarylalkenyl; wherein when R₂ is hydrogen. Yis —CH₂CHK₁, X is selected from the group consisting of —NZ— and —NH—,and R₁₂ is C₁-C₄ alkyl, wherein K₁ is selected from hydrogen and C₁-C₄alkyl and Z is C₁-C₄ alkyl, then R₄ is not arylalkyl.

R₄ is preferably selected from halogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl,heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,heteroarylalkyl, and heteroarylalkenyl, R₄ is more preferably selectedfrom halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl, R₄ is evenmore preferably selected from halogen, alkyl, alkenyl, and heteroalkyl.R₄ is most preferably selected from halogen and lower alkyl. The mostpreferred halogens for R₄ are chlorine, bromine, and iodine, preferablychlorine and iodine, and most preferably iodine. The most preferredlower alkyls for R₄ are methyl, ethyl, iso-propyl, and tert-butyl,preferably methyl, iso-propyl, and tert-butyl, more preferablyiso-propyl or tert-butyl. Most preferably, R₄ is lower alkyl,particularly iso-propyl or tert-butyl.

The Substituents R₈ and R₉

R₈ and R₉ are each, independently, selected from hydrogen, halogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl;wherein at least one of R₈ and R₉ is not hydrogen. Preferably, each ofR₈ and R₉ are not hydrogen.

R₈ and R₉ are preferably each, independently, selected from halogen,alkyl, alkenyl, heteroalkyl, and heteroalkenyl. R₈ and R₉ are morepreferably each, independently, selected from halogen, alkyl, alkenyl,and heteroalkyl. R₈ and R₉ are even more preferably each, independently,selected from halogen and lower alkyl. The most preferred halogens forR₈ and R₉ are chlorine and bromine, preferably chlorine. The mostpreferred lower alkyls for R₈ and R₉ are methyl, ethyl, iso-propyl, andtert-butyl, preferably methyl, iso-propyl, and tert-butyl, morepreferably methyl and iso-propyl. Most preferably, R₈ and R₉ are each,independently, selected from lower alkyl and halogen, particularlymethyl and chlorine, respectively.

The Substituent R₃

R₃ substitutes on the oxygen moiety of the biphenyl structure as shownabove. R₃ is selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl,heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,heteroarylalkyl and heteroarylalkenyl. Preferably, R₃ is selected fromhydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroalkyl,heteroalkenyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl. Morepreferably, R₃ is selected from hydrogen, alkyl, alkenyl, aryl,arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl. Still morepreferably, R₃ is selected from hydrogen, alkyl, alkenyl, arylalkyl(preferably benzyl), heteroalkyl, and heteroarylalkyl. Even morepreferably. R₃ is selected from hydrogen, lower alkyl, and loweralkenyl. Most preferably. R₃ is selected from hydrogen and lower alkyl.The most preferred lower alkyl for R₃ is methyl.

The Substituents R₆ and R₆′

R₆ and R₆′ are each, independently, selected from nil and oxo. Whereinboth R₆ and R₆′ are nil, then the sulfur-bridge of the compound is —S—.Wherein R₆ is nil and R₆′ is oxo (or wherein R₆ is oxo and R₆′ is nil),then the sulfur-bridge of the compound is a sulfoxide (—S(O)—). WhereinR₆ and R₆′ are both oxo, then the sulfur-bridge of the compound is asulfone (—S(O)(O)—).

The Substituent Y

Y is selected from bond, alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, and heteroalkynyl. Wherein Y is bond, X is directlybonded to the phenyl ring bearing R₇, R₈, R₉, and R₁₀. Y is preferablyselected from bond, alkyl, alkenyl, heteroalkyl, and heteroalkenyl. Morepreferably, Y is selected from bond and lower alkyl. Most preferably, Yis bond.

The Substituent X

X is selected from —NZ—, —NH—, and —O—. Z substitutes on the nitrogen of—NZ— and is selected from alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, and heteroalkynyl; or wherein when R₁₁ is bond, then R₁₂and Z may be optionally bonded together to form a cycle selected fromcycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,and heteroaryl. Preferably, Z is selected from alkyl, alkenyl,heteroalkyl, and heteroalkenyl, or R₁₂ and Z are bonded together to forma cycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, and heteroaryl. More preferably, Z is loweralkyl, or R₁₂ and Z are bonded together to form a cycle selected fromcycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,and heteroaryl. Most preferably, Z is C₁-C₃ alkyl, particularly methyl,or R₁₂ and Z are bonded together to form a cycle selected fromcycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,and heteroaryl.

Preferably, X is selected from —NE— and —NZ—. Most preferably, X is—NH—, —N(CH₃)—, or —NZ— wherein R₁₂ and Z are bonded together to form acycle selected from the group consisting of cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

Wherein R₁₂ is bonded to Z to form a cycle, the cycle is preferablyselected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, morepreferably from cycloalkyl, heterocycloalkyl, and aryl, even morepreferably from cycloalkyl and heterocycloalkyl, and most preferablyheterocycloalkyl. In addition to the optional substituents describedherein above, the cycle may also optionally bear one or more oxo (i.e.,doubly bonded oxygen) substituents. Non-limiting examples of thesecycles include piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl,indolinyl, succinimidyl, and hydantoinyl.

The Substituent R₁₁

R₁₁ is selected from bond and —C(O)—, wherein when Y is bond and X is—O—, then R₁₁ is —C(O)—. Wherein R₁₁ is bond, R₁₂ is directly bonded toX. While both bond and —C(O)— are both highly preferred for R₁₁, mostpreferably, R₁₁ is —C(O)—.

The Substituent R₁₂

R₁₂ is selected from alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, and heteroarylalkenyl; or wherein when R₁₁ is bond,then R₁₂ and Z may be optionally bonded together to form a cycleselected from the group consisting of cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl; wherein whenR₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl,then a heteroatom of R₁₂ is not directly covalently bonded to R₁₁.Accordingly, carbamates and ureas at the —Y—X—R₁₁-R₁₂ linkage are notcontemplated within the present invention. For example, wherein R₁₂ isheteroalkyl, it is not, e.g., —O—CH₂—CH₃, but could be, e.g.,—CH₂—O—CH₃.

Preferably, R₁₂ is selected from alkyl, alkenyl, heteroalkyl,heteroalkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, andheteroarylalkenyl, or is bonded to Z to form a cycle selected fromcycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,and heteroaryl. More preferably, R₁₂ is selected from alkyl, alkenyl,heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, and heteroarylalkenyl, or is bonded to Z to form acycle selected from cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, and heteroaryl. Even more preferably, R₁₂ isselected from alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, or isbonded to Z to form a cycle selected from cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Mostpreferably, R₁₂ is lower alkyl, or is bonded to Z to form a cycleselected from cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, and heteroaryl. The most preferred loweralkyls for R₁₂ are methyl, ethyl, n-propyl, iso-propyl, n-butyl,tert-butyl, and n-pentyl, particularly methyl, n-propyl, iso-propyl,n-butyl, and tert-butyl.

Wherein R₁₂ is bonded to Z to form a cycle, the cycle is preferablyselected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, morepreferably from cycloalkyl, heterocycloalkyl, and aryl, even morepreferably from cycloalkyl and heterocycloalkyl, and most preferablyheterocycloalkyl. In addition to the optional substituents describedherein above, the cycle may also optionally bear one or more oxo (i.e.,doubly bonded oxygen) substituents. Non-limiting examples of thesecycles include piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl,indolinyl, succinimidyl, and hydantoinyl.

Preferred compounds of the present invention are set forth in thefollowing tables:

TABLE 1 Preferred Compounds of the Present Invention In the followingpreferred compounds, R₆ and R₆ ^(′) are each nil:

TABLE 2 Preferred Compounds of the Present Invention In the followingpreferred compounds, R₆ is nil and R₆ ^(′) is oxo (or R₆ is oxo and R₆^(′) is nil):

TABLE 3 Preferred Compounds of the Present Invention In the followingpreferred compounds, R₆ and R₆ ^(′) are each oxo:

Analytical Methods

The present invention relates to compounds and methods for treating hairloss. Preferably, the compound utilized in the present invention will becardiac-sparing. Compounds (test compounds) may be tested for theirability to induce anagen and their lack of cardiotoxicity(cardiac-sparing) using the following methods. Alternatively, othermethods well-known in the art may be used (but with the term“cardiac-sparing” being defined according to the method disclosed hereinbelow).

Cardiotoxicity Assay:

The cardiotoxicity assay measures the potential of a test compound toadversely affect the cardiovascular system. As thyroid hormone (T3)damages the cardiovascular system, the heart enlarges. See, e.g.,Gomberg-Maitland et al., “Thyroid hormone and Cardiovascular Disease”,American Heart Journal, Vol. 135(2), pp. 187-196 (1998); Klein andOjamaa, “Thyroid Hormone and the Cardiovascular System”, Current Opinionin Endocrinology and Diabetes, Vol. 4, pp.341-346 (1997); and Klempereret al., “Thyroid Hormone Therapy and Cardiovascular Disease”, Progressin Cardiovascular Diseases, Vol. 37 (4), pp. 329-336 (1996). Thisincreases the weight of the heart relative to whole body weight. Thecardiotoxicity assay herein below is used to test compounds forpotentially adverse cardiac effects by measuring their effect on theheart-to-body weight ratio.

Two groups each of six male Sprague Dawley rats (Harlan Sprague Dawley,Inc., Indianapolis, Ind.) (each weighing from approximately 220 grams to235 grams) are utilized. The first group is a vehicle control group andthe second group is a test compound group. The length of the assay is 30days, with treatment of vehicle or test compound in vehicle daily for 28of those days as described below.

Prior to initiation of the assay, each rat is allowed to acclimate tostandard environmental conditions for 5 days. Each rat receives food(standard rat chow diet) and water ad libitum 5 days prior to initiationof the assay as well as to termination of the study.

The vehicle is 91:9 (v:v) propylene glycol:ethanol. The test compound isprepared at a concentration of 500 μg/mL in the vehicle.

Each rat is weighed on day 1 of the assay. Dosage calculations are thenperformed: each rat will be administered daily a dosing solution ofvehicle or test compound in vehicle (depending on whether the rat is inthe vehicle control group or the test compound group, respectively) at500 μL of dosing solution per kg of rat. For rats in the test compoundgroup, this corresponds to a dose of 250 μg of test compound per kg ofrat.

Day 2 is the first day of treatment with dosing solution for bothgroups. Body weights are taken for each rat on days 3, 5, 8, 10, 12, 15,17, 19, 22, 24, 26, and 29 prior to dosing for that day; for each rat,the dosing solutions are recalculated and administered accordingly uponchange in body weight.

Treatment occurs once daily in the morning on days 2 through 29,inclusive, for each rat in each group. For each treatment, the dosingsolution is administered subcutaneously between the shoulders of the ratsuch that the injection sites are rotated in this area.

On day 30 in the morning, the rats of each group are euthanized with CO₂from dry ice. Each rat is immediately weighed for total body weight.

The hearts of each rat are then excised as follows. An incision is madeto expose the abdominal cavity. The rib cage is carefully cut at thesternum with small scissors, such that the heart and lungs are exposed.With small scissors and forceps, the vessels connected to the heart arecut away from the heart. These vessels include the caudal vena cava,left cranial vena cava (pulmonary trunk), right cranial vena cava,thoracic aorta, right subclavian artery, internal thoracic artery andvein, and any other small attachments. The heart is then immediatelytaken out intact, including the left and right auricles and left andright ventricles. Immediately thereafter, any excess tissue is trimmedaway, the heart is lightly blotted on a paper towel until no more bloodis visibly left behind on the paper towel, and the heart is weighed.

The heart weight is divided by the body weight after euthanization foreach rat to give the heart/body ratio. The heart/body ratios for eachrat in the vehicle control group are added together and divided by 6(i.e., the total number of rats in the group) to give RV (ratio forvehicle control group). Similarly, the heart/body ratios for each rat inthe test compound group are added together and divided by 6 to give RT(ratio for test compound group).

The index C is then calculated by dividing RT by RV. As defined herein,where C is less than 1.3, the test compound is cardiac-sparing.Preferably. C is less than 1.2, more preferably less than 1.15, and mostpreferably less than 1.1. In accordance with this method, T3 and T4 arenot cardiac-sparine.

Telogen Conversion Assay:

The Telogen Conversion Assay measures the potential of a test compoundto convert mice in the resting stage of the hair growth cycle(“telogen”), to the growth stage of the hair growth cycle (“anagen”).

Without intending to be limited by theory, there are three principalphases of the hair growth cycle: anagen, catagen, and telogen. It isbelieved that there is a longer telogen period in C3H mice (HarlanSprague Dawley, Inc., Indianapolis. Ind.) from approximately 40 days ofage until about 75 days of age, when hair growth is synchronized. It isbelieved that after 75 days of age, hair growth is no longersynchronized. Wherein about 40 day-old mice with dark fur (brown orblack) are used in hair growth experiments, melanogenesis occurs alongwith hair (fur) growth wherein the topical application of hair growthinducers are evaluated. The Telogen Conversion Assay herein below isused to screen compounds for potential hair growth by measuringmelanogenesis.

Three groups of 44 day-old C3H mice are utilized: a vehicle controlgroup and a test compound group, wherein the test compound group isadministered a compound according to the present invention. The lengthof the assay is at least 19 days with 15 treatment days (wherein thetreatment days occur Mondays through Fridays). Day 1 is the first day oftreatment. Most studies will end on Day 19, but a few may be carried outto Day 24 if the melanogenesis response looks positive, but occursslowly. A typical study design is shown in Table 4 below. Typical dosageconcentrations are set forth in Table 4, however the ordinarily skilledartisan will readily understand that such concentrations may bemodified.

TABLE 4 Applica- Group Animal Concen- tion Length of # # Compoundtration volume Study 1  1-10 Test 0.1% in 400 μL 19 or 24 days Compoundvehicle** topical 2 11-20 Positive 0.01% in 400 μL 19 or 24 days Control(T3) vehicle** topical 3 21-30 Vehicle** N/A 400 μL 19 or 24 daystopical **The vehicle is 60% ethanol, 20% propylene glycol, and 20%dimethyl isosorbide (commercially available from Sigma Chemical Co., St.Louis, MO).

The mice are treated topically Monday through Friday on their lower back(base of tail to the lower rib). A pipettor and tip are used to deliver400 μL to each mouse's back. The 400 μL application is applied slowlywhile moving hair on the mouse to allow the application to reach theskin.

While each treatment is being applied to the mouse topically, a visualgrade of from 0 to 4 will be given to the skin color in the applicationarea of each animal. As a mouse converts from telogen to anagen, itsskin color will become more bluish-black. As indicated in Table 5, thegrades 0 to 4 represent the following visual observations as the skinprogresses from white to bluish-black.

TABLE 5 Visual Observation Grade Whitish Skin Color 0 Skin is light gray(indication of initiation of anagen) 1 Appearance of Blue Spots 2 BlueSpots are aggregating to form one large blue area 3 Skin is dark blue(almost black) with color covering majority 4 of treatment area(indication of mouse in full anagen)

Methods of Making

The compounds of the present invention are prepared according to,methods which are well-known to those ordinarily skilled in the art. Thestarting materials used in preparing the compounds of the invention areknown, made by known methods, or are commercially available as astarting material.

It is recognized that the ordinarily skilled artisan in the art oforganic chemistry can readily carry out standard manipulations oforganic compounds without further direction. Examples of suchmanipulations are discussed in standard texts such as J. March, AdvancedOrganic Chemistry, John Wiley & Sons, 1992.

The ordinarily skilled artisan will readily appreciate that certainreactions are best carried out when other functionalities are masked orprotected in the compound, thus increasing the yield of the reactionand/or avoiding any undesirable side reactions. Often, the ordinarilyskilled artisan utilizes protecting groups to accomplish such increasedyields or to avoid the undesired reactions. These reactions are found inthe literature and are also well within the scope of the ordinarilyskilled artisan. Examples of many such manipulations can be found in,for example, T. Greene, Protecting Groups in Organic Synthesis, JohnWiley & Sons, 1981.

The compounds of the present invention may have one or more chiralcenter. As a result, one may selectively prepare one optical isomer,including diastereomers and enantiomers, over another, for example bychiral starting materials, catalysts or solvents, or may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastercomers and enantiomers, or stereoisomers may beseparated using known methods, such as through the use of, for example,chiral salts and chiral chromatography.

In addition, it is recognized that one optical isomer, including adiastereomer and enantiomer, or a stereoisomer, may have favorableproperties over the other. Thus, when disclosing and claiming theinvention, when one racemic mixture is disclosed, it is clearlycontemplated that both optical isomers, including diastercomers andenantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

The compounds of the present invention may be prepared using a varietyof procedures known to those ordinarily skilled in the art. Non-limitinggeneral preparations include the following.

The compounds of the invention can be prepared, after removal oftemporary protection groups (see, e.g., T. Greene, Protecting Groups inOrganic Synthesis, John Wiley & Sons, 1981) by condensing (e.g.,acylating or alkylating) a compound of the structure:

wherein R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀, Y, and X are defined hereinabove and are in an appropriately protected form if necessary, with areactive derivative of the structure:

wherein R₁₂ is defined herein above and is in an appropriately protectedform if necessary and Q is halogen, preferably bromine or iodine, andmost preferably iodine. Reactive derivatives of structure II include,for example, activated esters such as 1-hydroxybenzotriazole esters,mixed anhydrides of organic or inorganic acids such as hydrochloric acidand sulfonic acids, and symmetrical anhydrides of the acids of structureII. Activated derivatives of structure III include trifluoromethanesulfonyl esters and other activated derivatives known to thoseordinarily skilled in the art.

Compounds of structure Iv are generally appropriately reactive withoutfurther modification; however, it may be necessary to convert a lessreactive halogen to a more reactive halogen such as bromine or iodine asis known by those ordinarily skilled in the art. Many appropriatelyactivated derivatives of structure II, III, or IV are commerciallyavailable and others can be prepared by methods known to thoseordinarily skilled in the art. Non-limiting examples of condensations ofthis type are provided in Examples 2, 3, 4, 5, 7, 9, and 10.

Additionally, appropriately protected compounds resulting from thecondensation of a compound of structure I with a compound of structureII, III or IV may be further modified to afford additional compounds ofthe invention after removal of temporary protection groups. Thesemodifications include, but are not limited to, reduction of an amide toan amine as described in Example 6 to afford a secondary or tertiaryamine, and alkylation of an amide as described in Example 6.

Furthermore, compounds of the invention, in an appropriately protectedform if necessary and having the thioether linkage, may be oxidizedusing conditions known to those ordinarily skilled in the art to affordsulfones of the structure V and sulfoxides of the structure VI (seestructures below), also compounds of the invention after removal oftemporary protection groups. A specific example of the oxidation of athioether to the sulfone using tert-butylhydroperoxide is described inExample 13 and specific examples of the oxidation of a thioether to thesulfoxide using 3-chloroperoxybenzoic acid are described in Examples 11and 12.

Additionally, compounds of the structure I may be prepared from a biarylthioether intermediate of structure VII wherein P is, for example, anitro, cyano, or acyl group.

Compounds of the structure VII may be prepared by condensing a4-halonitrobenzene of structure VIII with an appropriately substitutedphenol of structure IX in a base catalyzed reaction as described inExamples 1, 7 and 8 below wherein Q is preferably chlorine or bromine.

Compounds of the structure VII can be converted to compounds of thestructure I by further transformation. For example, wherein P is nitro,the resulting compound of structure VII may be converted into a compoundof structure I by reduction to the amine using standard chemicalreactions. Wherein P is an acyl group, the compounds may be converted tocompounds of structure I having secondary or tertiary amines byreductive alkylation of the ketone with a primary or secondary amine anda borohydride reducing reagent in a solvent such astrimethylorthoformate using conditions known to those ordinarily skilledin the art.

For even further guidance, the following non-limiting examplesillustrate more specifically the methods of making various compounds ofthe present invention.

As used herein, the following abbreviations are used:

Tetrahydrofuran THF N,N-Dimethylformamide DMF N-tert-butoxycarbonyl BOCN,N-diisopropylethylamine i-Pr₂NEt or i-Pr₂EtN Trifluoroacetic acid TFA18-Crown-6 1, 4, 7, 10, 13, 16- hexaoxacyclooctadecane

Example 1

1a. 2-iso-propyl anisole: Potassium hydroxide (5.6 g) is added to 13.4mL acetone followed by 2-iso-propylphenol (13.6 g). After the potassiumhydroxide is dissolved, methyl iodide (14.2 g) is added. The reaction isrefluxed overnight, 150 mL of water is added. This reaction is extracted3 times with 100 mL diethyl ether. The organic layer is extracted twicewith 100 mL 10% sodium hydroxide in water, once with 100 mL water, andonce with 100 mL saturated ammonium chloride. After drying overmagnesium sulfate, the organic solution is dried over MgSO₄, filtered,and concentrated under reduced pressure. The material is fractionallydistilled under reduced pressure to afford 1a.

1b. 3-iso-propyl-4-methoxyiodobenzene: Potassium iodide (8.85 g) issuspended in 80 mL of dichloromethane. The mixture is cooled to 0° C.and then 18-crown-6 (0.7 g) in 20 mL dichloromethane is added. In 100 mLdichloromethane, 3-chioroperbenzoic acid is added. To this mixture isadded 2-iso-propyl anisole (1a; 4 g) dropwise. The reaction is stirredfor 3 hours in a 0° C. bath and then is poured into 300 mL of ice waterand stirred for an additional 30 minutes. At this time, the organiclayer is isolated and washed with 200 mL saturated sodium hydrogencarbonate solution, followed by 200 mL water, and is dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The compound is purified by chromatography on silica gel (hexane:ethylacetate) to afford 1b.

1c. Copper (I) thiobenzoate: Copper (II) acetate (3 g) is dissolved in100 mL glacial acetic acid. Thiobenzoic acid (1.25 g) is dissolved in 25mL glacial acetic acid and this is poured into the copper (II) acetatesolution. Precipitate is formed and is isolated by filtration. The solidis washed with acetic acid, water, and ethanol, and then dried underreduced pressure to afford 1c.

1d. S-benzoyl-3-iso-propyl-4-methoxythiophenol: Copper (I) thiobenzoate(1c; 0.141 g) and 3-iso-propyl-4-methoxyiodobenzene (0.6 g) aredissolved in 9 mL hexamethylphosphoramide. The reaction is heated atabout 100° C. for 2 hours and then poured into 500 mL water. The mixtureis stirred until precipitation is complete and the precipitate isisolated and washed with water and air dried. This material is extractedin a Soxhlet extractor using benzene and concentrated under reducedpressure. The residue is triturated with hexane to afford 1d. Thematerial can be further purified by crystallization from ethylacetate:hexane.

1e. 3-iso-propyl-4-methoxythiophenol:S-benzoyl-3-iso-propyl-4-methoxythiophenol (0.5 g) in 25 mL 10% aqueoussodium hydroxide and 2.5 mL ethanol is heated to reflux under nitrogenfor about 16 hours. The mixture is cooled and extracted once with ethylacetate. The aqueous phase is acidified with 6 N HCl and then extractedtwice with ethyl acetate. The organic layers are combined and washedwith water and brine then dried over sodium sulfate and filtered. Thefiltrate is concentrated under reduced pressure and purified bychromatography on silica gel (hexane:ethyl acetate) to afford 1e.

1f. 4-chloro-3,5-dimethyl-nitrobenzene: 2′,6′-dimethyl-4-nitrophenol (3g) is added to 50 mL dichloromethane followed by addition of 3.6 mLpyridine. The solution is cooled to 0° C. and 3.6 mLtrifluoromethanesulfonic anhydride is added dropwise over 20 minutes.The reaction is mixed for about 3 hours at 0° C. 25 mL water is added toquench the reaction. The organic layer is extracted twice with 25 mL 1Nhydrochloric acid, twice with 25 mL water, twice with 25 mL 1N sodiumhydroxide, twice with 25 mL water, dried with magnesium sulfate, andconcentrated under reduced pressure. The remaining residue is dissolvedin 40 mL of DMF followed by addition of lithium chloride (2.4 g). Themixture is refluxed for 17 hours at 150° C. The mixture is concentratedunder high vacuum. To this residue, 60 mL water and 60 mL ethyl acetateis added and stirred. This mixture is filtered, the organic layerseparated, and dried with magnesium sulfate. The organic layer isconcentrated under high vacuum and the remaining residue presorbed tosilica gel using dichloromethane. The presorbed residue is then purifiedby chromatography on silica gel (hexane:ethyl acetate) and subsequentlycrystallized from hexanes to afford 1f.

1g. 3,5-dimethyl-4-(4′-methoxythiophenoxy)-nitrobenzene:4-chloro-3,5-dimethyl-nitrobenzene (1f; 175 mg) and3-iso-propyl-4-methoxythiophenol (1e; 139 mg) are dissolved into 7.5 mLmethylsulfoxide. To this solution, anhydrous potassium carbonate (153mg) is added and the reaction is mixed under nitrogen for 23 hours at128° C. The reaction is precipitated by the addition of 50 mL ice water.The mixture is then extracted with 75 mL ethyl acetate. The organiclayer is extracted once with 50 mL brine solution, dried with magnesiumsulfate, and concentrated under high vacuum to afford 1g.

1h. 2′,6′-dimethyl-3-iso-propyl-4-methoxy-4′-aminodiphenylthioether:3.5-dimethyl-4-(4′-methoxythiophenoxy)-nitrobenzene (1g, 200 mg) isdissolved in 15 mL ethanol and 10% palladium on carbon is added. Thereaction is hydrogenated, then filtered through Celite and concentratedunder reduced pressure to afford 1h. Alternatively,3.5-dimethyl-4-(4′-methoxythiophenoxy)-nitrobenzene (1g; 0.33 g) isdissolved in 5 mL of 49:1 ethanol:ethyl acetate by heating on a waterbath (40° C.) and to this solution, tin chloride dihydrate (1 g) isadded. The reaction is heated to 70° C. and stirred for about 2 hours.The reaction is allowed to cool to room temperature, then poured ontoice. The pH is made slightly basic (pH 7-8) by addition of 5% aqueoussodium bicarbonate (50 mL) and then extracted with ethyl acetate (50mL). The organic phase is washed with brine (50 mL), treated withcharcoal, dried over MgSO₄, and filtered. The filtrate is evaporated toprovide 1h.

1j. 3-iso-propyl-4-methoxyphenol: Acetyl chloride (5.9 mL) is added to200 mL dichloromethane. To this solution is addedtrifluoromethanesulfonic anhydride (7.4 mL). After stirring for about 6minutes, the, 2-iso-propylanisole (1a; 10 g) is added in one portion.The reaction is kept in an room temperature water bath. The reactionstirs for about 16 hours and is then concentrated under reducedpressure. The material is taken up in 400 mL ethyl acetate. This iswashed with 400 mL water, then 250 mL saturated sodium bicarbonate andfinally 250 mL saturated NaCl solution. The organic layer is dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thismaterial is recrystallized from heptane. The crystals are dissolved in50 mL glacial acetic acid and placed in a 9° C. water bath and thereaction is stirred for 30 minutes. Peracetic acid, 32% in dilute aceticacid (29 mL) is added. The reaction is stirred in the water bathovernight, rising to room temperature. In the morning, the bath ischanged to an ice water bath and the solution equilibrates for about 30minutes. At this time, a sodium bisulfite solution (13.73 g in 48 mLwater) is added dropwise. The reaction is stirred for 1 hour and pouredinto a separatory funnel. The aqueous layer is extracted with 250 mLhexanes. The organic layer is separated and the aqueous layer isextracted two more times with 100 mL hexanes. The organic layers arecombined and back extracted with 3×100 mL water, once with 150 mL brineand is dried over sodium sulfate and concentrated under reducedpressure. The material is dissolved in methanol (68 mL) and stirred. Thesolution is cooled in an ice bath and 1N sodium hydroxide solution (68.4mL) and is added dropwise. The ice bath is removed and the reaction isallowed to warm to room temperature and stir for 3 hours. The reactionis concentrated under reduced pressure and taken up in 250 mL ethylacetate and extracted with 100 mL 1N NaOH twice, 100 mL water, and 100mL brine. The solution is dried over sodium sulfate and concentratedunder reduced pressure to afford 1j.

1k. 2-iso-propyl-4-(N,N-dimethylthiocabamoloxy)anisole:N,N-dimethylthiocarbamoyl chloride (10.9 g),3-iso-propyl-4-methoxyphenol (1j; 10 g) and1,4-diazabicyclo[2.2.2]octane (13.4 g) are combined in 250 mL DMF. Thereaction is heated with stirring at 70° C. for one hour. At this time,the reaction is cooled to room temperature and filtered. The filtrate isconcentrated under reduced pressure and the resulting solid is washedwell with water and dried to afford 1k.

1l. 2-iso-propyl-4-(N,N-dimethylcabamoylthio)anisole:2-iso-propyl-4-(N,N-dimethylthiocabamoyloxy) anisole, 6 g, is heatedunder a nitrogen atmosphere at 230° C. for one hour. At this time, thereaction is cooled to room temperature and the product is purified bychromatography on silica gel (hexane:ethyl acetate) to afford 1L.

1e. 3-iso-propyl-4-methoxythiophenol:2-iso-propyl-4-(N,N-dimethylcabamoylthio)anisole (2 g) in 100 mL 10%aqueous sodium hydroxide and 10 mL ethanol is heated to reflux undernitrogen overnight. At this time, it is cooled and extracted once withethyl acetate. The aqueous phase is acidified with 6 N HCl and thenextracted twice with ethyl acetate. The organic layers are combined andwashed with water and brine then dried over sodium sulfate and filtered.The filtrate is concentrated under reduced pressure and purified bychromatography on silica gel (hexane:ethyl acetate) to afford 1e.

Example 2

2.N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]butyramide:2′,6′-dimethyl-3-iso-propyl-4-methoxy-4′-aminodiphenylthioether (1h;0.23 g) is suspended in pyridine, 0.12 mL, and butyric anhydride (0.23mL) is added. The reaction is allowed to proceed for two hours and thenit is concentrated under reduced pressure. The resulting residue ispresorbed onto silica gel using acetone and purified by chromatographyon silica gel (hexanes:ethyl acetate). The product is crystallized fromhexanes to afford 2.

Example 3

3.N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]pyrrolidine:2′,6′-dimethyl-3-iso-propyl-4-methoxy-4′-aminodiphenylthioether (1h;1.58 g) is dissolved in 2 mL ethanol and 0.75 mL 1,4-diiodobutane isadded. The sample is refluxed overnight. At this time, it isconcentrated under reduced pressure. The sample is taken up in ethylacetate and extracted with 0.1 N sodium hydroxide, water, and brine.After drying over sodium sulfate, filtering and concentration underreduced pressure, it is purified by chromatography on silica gel(hexane:ethyl acetate) to afford 3.

Example 4

4.N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]benzamide:2′,6′-dimethyl-3-iso-propyl-4-methoxy-4′-aminodiphenylthioether (1h;0.245 g) is suspended in pyridine (1 mL). To this solution is added 0.24mL benzoyl chloride and the reaction is stirred 1 hour. The sample isconcentrated under reduced pressure and dissolved in ethyl acetate. Thisis washed with water and brine then dried over magnesium sulfate andconcentrated under reduced pressure. The residue is recrystallized fromethyl acetate:hexanes to afford 4.

Example 5

5.N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]-2-methylpropionamide:Iso-butyric anhydride (4 mL) is added to2′,6′-dimethyl-3-iso-propyl-4-methoxy-4′-aminodiphenylthioether (1h;0.225 g) and the reaction is stirred overnight. At this time, 20 mLwater and 20 mL ethyl acetate are added and the reaction mixture isextracted with 1 N NaOH until the aqueous layer has a pH above 10. Afterextracting once with brine, drying over magnesium sulfate and filtering,the organic layer is concentrated under reduced pressure and purified bychromatography on silica gel (hexane:ethyl acetate) to afford 5.

Example 6

6a.N-methyl-N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]butyramide:In a dry flask under nitrogen, 0.32 g sodium hydride is suspended in 5mL THF and stirred 10 minutes. To this solution is added dropwiseN-(3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl)butyramide(2; 1 g) in 5 mL THF. The reaction is stirred for 15 minutes and methyliodide (0.28 mL) is added dropwise. After 2 hours, the reaction ispoured into ice water and extracted with chloroform. The organic layeris washed once with water, once with brine then dried over magnesiumsulfate and concentrated under reduced pressure. The product is purifiedby chromatography on silica gel (hexanes:ethyl acetate) to afford 6a.

6b.N-methyl-N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]butylamine:In a dry flask under nitrogen is placed lithium aluminum hydride (1 g).To this is added 30 mL THF dropwise. After stirring 10 minutes, asolution ofN-methyl-N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl)butyramide(6a, 1.36 g) in 6 mL THF is added dropwise and the reaction is refluxedfor about 16 hours. At this time, the reaction is cooled in an ice bathand 12 mL water is added dropwise followed by dropwise addition of 12 mL15% sodium hydroxide, then 60 mL water. The reaction is stirred for 90minutes. At this time, it is filtered through celite and washed with THFand ethyl acetate. The filtrate is concentrated under reduced pressureand the product is purified by chromatography on silica gel(hexane:ethyl acetate) to afford 6b.

Example 7

7a. 2′,6′-dichloro-3-iso-propyl-4-methoxy-4′-nitrodiphenyl thioether:Potassium carbonate (6.8 g) is suspended in methylsulfoxide (100 mL).1,2,3-trichloro-5-nitrobenzene (9.9 g) is added followed by3-iso-propyl-4-methoxythiophenol (1e; 8 g). The reaction is heated to37° C. and stirred under nitrogen with a mechanical stirrer for 20hours. At this time, 200 mL cold water is added while stirring. Afterstirring for 2 hours the reaction mixture is filtered through a mediumporosity frit and the filter cake is dried under reduced pressure toafford 7a.

7b. 3,5-dichloro-4-(4′-methoxy-3′-iso-propylthiophenoxy)benzylamine:2′,6′-dichloro-3-iso-propyl-4-methoxy-4′-nitrodiphenyl thioether (7a;0.35 g) is dissolved in 5 mL of 49:1 ethanol:ethyl acetate by heating ona water bath (40° C.) and to this solution, tin chloride dihydrate (1 g)is added. The reaction is heated to 70° C. and stirred for about 1.5hours. The reaction is allowed to cool to room temperature, then pouredonto ice. The pH is made slightly basic (pH 7-8) by addition of 5%aqueous sodium bicarbonate (50 mL) and then extracted with ethyl acetate(50 mL). The organic phase is washed with brine (50 mL), treated withcharcoal, dried over MgSO₄, and filtered. The filtrate is evaporated toprovide 7b. Alternatively,2′,6′-dichloro-3-iso-propyl-4-methoxy-4′-nitrodiphenyl thioether (7a;0.4 g) is dissolved in 15 mL 1:1 ethyl acetate:ethanol and 60 mg of 10%palladium on carbon is added. The reaction is hydrogenated, thenfiltered through Celite and concentrated under reduced pressure toafford 7b.

7c.N-[3,5-dichloro-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]butyramide:3.5-dichloro-4-(4′-methoxy-3′-iso-propylthiophenoxy)benzylamine (7b,0.22 g) is suspended in pyridine, 0.12 mL, and butyric anhydride (0.23mL) is added. The reaction is allowed to proceed for two hours and thenit is concentrated under reduced pressure. The resulting residue ispresorbed onto silica gel using acetone and purified by chromatographyon silica gel (hexanes:ethyl acetate) to afford 7c.

Example 8

8a. 3-tert-butyl-4-methoxythiophenol: 3-tert-butyl-4-methoxythiophenol(8a) is prepared analogously to the synthesis of3-iso-propyl-4-methoxythiophenol (1e), which is described above, bysubstituting 2-tert-butyl phenol as a starting material for 2-iso-propylphenol.

8b. 3,4-dichloro-5-methyl-nitrobenzene:3,4-dichloro-5-methyl-nitrobenzene (8b) is prepared analogously to thesynthesis of 4-chloro-3,5-dimethyl-nitrobenzene (1f), which is describedabove, by substituting 2-chloro-4-nitro-6-methylphenol for2,6-dimethyl-4-nitrophenol.

8c.3-chloro-5-methyl-4-(3′-tert-butyl-4′-methoxythiophenoxy)-nitrobenzene:3,4-dichloro-5-methyl-nitrobenzene (8b; 195 mg) and3-tert-butyl-4-methoxythiophenol (8a; 150 mg) are dissolved into 7.5 mLmethylsulfoxide. To this solution, anhydrous potassium carbonate (150mg) is added and the reaction mixed under nitrogen for 23 hours at 80°C. 50 mL ice water is added. The mixture is then extracted with 75 mLethyl acetate. The organic layer is extracted once with 50 mL brinesolution, dried with magnesium sulfate, and concentrated under highvacuum to afford 8c.

8d.2′-chloro-6′-methyl-3-tert-butyl-4-methoxy-4′-aminodiphenylthioether:2′-chloro-6′-methyl-3-tert-butyl-4-methoxy-4′-aminodiphenylthioether(8d) is prepared analogously to the synthesis of3,5-dichloro-4-(4′-methoxy-3′-iso-propylthiophenoxy)benzylamine (7b),which is described above, by substituting3-chloro-5-methyl-4-(3′-tert-butyl-4′-methoxythiophenoxy)-nitrobenzene(8c) for 2′,6′-dichloro-3-iso-propyl-4-methoxy-4′-nitrodiphenylthioether (7a).

Example 9

9.N-(3-chloro-5-methyl-4-(4′-methoxy-3′-tert-butylthiophenoxy)phenyl)acetamide:Acetic anhydride (4 mL) is added to2′-chloro-6′-methyl-3-tert-butyl-4-methoxy-4′-aminodiphenylthioether(8d, 0.25 g) and the reaction is stirred overnight. At this time, 20 mLwater and 20 mL ethyl acetate are added and the reaction mixture isextracted with 1 N NaOH until the aqueous layer has a pH above 10. Afterextracting once with brine, drying over magnesium sulfate and filtering,the organic layer is concentrated under reduced pressure and purified bychromatography on silica gel (hexane:ethyl acetate) to afford 9.

Example 10

10.N-[3,5-dichloro-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]morpholine:3,5-dichloro-4-(4′-methoxy-3′-iso-propylthiophenoxy)benzylamine (7b;0.25 g) is dissolved in 2 mL ethanol and 0.15 g di(2-iodoethyl)ether isadded. The sample is refluxed overnight. At this time, it isconcentrated under reduced pressure. The sample is taken up in ethylacetate and extracted with 0.1 N sodium hydroxide, then water and brine.After drying over sodium sulfate, filtering, and concentrating thefiltrate under reduced pressure, it is purified by chromatography onsilica gel (hexanes:ethyl acetate) to afford 10.

Example 11

11.N-[3-chloro-5-methyl-4-(4′-methoxy-3′-tert-butylphenylsulfonyl)phenyl]acetamide:N-[3-chloro-5-methyl-4-(4 -methoxy-3-tert-butylthiophenoxy)phenyl]acetamide (9; 0.5 g) and 50%3-chloroperoxybenzoic acid (1 g) in dichloromethane is stirred for 20hours. At this time, the reaction is treated with aqueous sodiumbisulfite to quench excess peracid, then the organic layer is isolatedand washed with saturated sodium carbonate, water, brine and dried oversodium sulfate. The solution is filtered, the filtrate is concentratedunder reduced pressure, and the product is purified by chromatography onsilica gel (hexanes:ethyl acetate) to afford 11.

Example 12

12.N-[3,5-dichloro-4-(4′-methoxy-3′-iso-propylphenylsulfonyl)phenyl]morpholine:N-[3,5-dichloro-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]morpholine(10; 0.25 g) and 50% 3-chloroperoxybenzoic acid (0.46 g) indichloromethane is stirred for 20 hours. At this time, the reaction istreated with aqueous sodium bisulfite to quench excess peracid, then theorganic layer is isolated and washed with saturated sodium carbonate,water, brine and dried over sodium sulfate. The solution is filtered,the filtrate is concentrated under reduced pressure, and the product ispurified by chromatography on silica gel (hexanes:ethyl acetate) toafford 12.

Example 13

13.N-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenylsulfonyl)phenyl]butyramide:A mixture ofN-[3,5-dimethyl-4-(4′-methoxy-3′-iso-propylthiophenoxy)phenyl]butyramide(2; 1.1 g), 1.2 mL 5M tert-butylhydroperoxide in nonane, and 70 mgcamphor sulphonic acid are taken up in 15 mL dichloromethane and stirredfor 20 hours. At this time, the reaction mixture is poured directly ontoa silica gel column and the product is isolated by chromatography withhexanes:ethyl acetate.

Use of the Present Compounds

According to the methods of the present invention, a compound having astructure as described herein is administered, most preferably with apharmaceutically-acceptable or cosmetically-acceptable carrier.

The compounds of the present invention may be used for the treatment ofsuch conditions as treating hair loss in mammals, including arrestingand I or reversing hair loss and promoting hair growth. Such conditionsmay manifest themselves in, for example, alopecia, including malepattern baldness and female pattern baldness.

In addition, the compounds of the present invention may be useful forweight control, including the treatment and/or prevention of obesity.Other uses for the compounds of the present invention includestimulation of nail growth, treatment of skin conditions, prevention ofhair discoloration, obesity, cholesterol lowering, treatment of thyroiddisorders, and treatment of osteoporosis.

Preferably the compounds of the present invention are, as, definedherein, cardiac-sparing.

Preferably, the compounds are formulated into pharmaceutical or cosmeticcompositions for use in treatment or prophylaxis of conditions such asthe foregoing. Standard pharmaceutical formulation techniques are used,such as those disclosed in Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa. (1990).

Typically, from about 5 mg to about 3000 mg, more preferably from about5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg,of a compound having a structure as described herein is administered perday for systemic administration. It is understood that these dosageranges are by way of example only, and that daily administration can beadjusted depending on various factors. The specific dosage of thecompound to be administered, as well as the duration of treatment, andwhether the treatment is topical or systemic are interdependent. Thedosage and treatment regimen will also depend upon such factors as thespecific compound used, the treatment indication, the efficacy of thecompound, the personal attributes of the subject (such as, for example,weight, age, sex, and medical condition of the subject), compliance withthe treatment regimen, and the presence and severity of any side effectsof the treatment.

According to the present invention, the subject compounds areco-administered with a pharmaceutically-acceptable orcosmetically-acceptable carrier (herein collectively described ascarrier′). The term “carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with a compound of thepresent invention, and with each other, in a manner such that there isno interaction which would substantially reduce the efficacy of thecomposition under ordinary use situations. Carriers must, of course, beof sufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the animal, preferably mammal (mostpreferably human), being treated. The carrier can itself be inert or itcan possess pharmaceutical and/or cosmetic benefits of its own.

The compositions of this invention may be in any of a variety of forms,suitable (for example) for oral, rectal, topical, nasal, ocular orparenteral administration. Of these, topical and/or oral administrationare especially preferred with topical being most preferred. Dependingupon the particular route of administration desired, a variety ofcarriers well-known in the art may be used. These include solid orliquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active orcosmetically-active materials may be included which do not substantiallyinterfere with the activity of the compound of the present invention.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references: ModernPharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2^(nd) Ed., (1976).

Some examples of substances which can serve as carriers or componentsthereof are sugars, such as lactose, glucose and sucrose; starches, suchas corn starch and potato starch; cellulose and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose;powdered tragacanth; malt; gelatin; talc; solid lubricants, such asstearic acid and magnesium stearate; calcium sulfate; vegetable oils,such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil andoil of theobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a carrier to be used in conjunction with the subjectcompound is typically determined by the way the compound is to beadministered.

In particular, carriers for systemic administration include sugars,starches, cellulose and its derivatives, malt, gelatin, talc, calciumsulfate, vegetable oils, synthetic oils, polyols, alginic acid,phosphate buffer solutions, emulsifiers, isotonic saline, andpyrogen-free water. Preferred carriers for parenteral administrationinclude propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesameoil. Preferably, the carrier, in compositions for parenteraladministration, comprises at least about 90% by weight of the totalcomposition.

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, and preferablyfrom about 25% to about 50%, of a compound used in the presentinvention. Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed, containing suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquid oraldosage forms include aqueous solutions, emulsions, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules, and effervescent preparations reconstituted from effervescentgranules, containing suitable solvents, preservatives, emulsifyingagents, suspending agents, diluents, sweeteners, melting agents,coloring agents and flavoring agents.

The carriers suitable for the preparation of unit dosage forms for oraladministration are well-known in the art. Tablets typically compriseconventional pharmaceutically-compatible adjuvants as inert diluents,such as calcium carbonate, sodium carbonate, mannitol, lactose andcellulose; binders such as starch, gelatin and sucrose; disintegrantssuch as starch, alginic acid and croscarmelose; lubricants such asmagnesium stearate, stearic acid and talc. Glidants such as silicondioxide can be used to improve flow characteristics of the powdermixture. Coloring agents, such as the FD&C dyes, can be added forappearance. Sweeteners and flavoring agents, such as aspartame,saccharin, menthol, peppermint, and fruit flavors, are useful adjuvantsfor chewable tablets. Capsules (including time release and sustainedrelease formulations) typically comprise one or more solid diluentsdisclosed above. The selection of carrier components depends onsecondary considerations like taste, cost, and shelf stability, whichare not critical for the purposes of the subject invention, and can bereadily made by a person ordinarily skilled in the art.

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The carriers suitable for preparation of such compositionsare well known in the art. Typical components of carriers for syrups,elixirs, emulsions and suspensions include ethanol, glycerol, propyleneglycol, polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose. AVICEL RC-591, tragacanth and sodium alginate;typical wetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

The compounds of the present invention may also be topicallyadministered. The carrier of the topical composition preferably aidspenetration of the present compounds into the skin to reach theenvironment of the hair follicle. Topical compositions of the presentinvention may be in any form including, for example, solutions, oils,creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hairconditioners, milks, cleansers, moisturizers, sprays, skin patches, andthe like.

Topical compositions containing the active compound can be admixed witha variety of carrier materials well known in the art, such as, forexample, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin Aand E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate,and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glycerylmonostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetylalcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate,isocetyl stearate, oleyl alcohol, iso-propyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate,iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethyleneglycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachisoil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil,butyl myristate, isostearic acid, palmitic acid, iso-propyl linoleate,lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate;propellants, such as propane, butane, iso-butane, dimethyl ether, carbondioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylenechloride, iso-propanol, castor oil, ethylene glycol monoethyl ether,diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,methylsulfoxide, dimethyl formamide, tetrahydrofuran; humectants, suchas glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, solublecollagen, dibutyl phthalate, and gelatin; and powders, such as chalk,talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide,sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl arylammonium smectites, chemically modified magnesium aluminium silicate,organically modified montmorillonite clay, hydrated aluminium silicate,fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, andethylene glycol monostearate.

The compounds used in the present invention may also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines. A preferredformulation for topical delivery of the present compounds utilizesliposomes such as described in Dowton et al., “Influence of LiposomalComposition on Topical Delivery of Encapsulated Cyclosporin A: I. An invitro Study Using Hairless Mouse Skin”, S.T.P. Pharma Sciences, Vol. 3,pp. 404-407 (1993); Wallach and Philippot, “New Type of Lipid Vesicle:Novasome®”, Liposome Technology, Vol. 1, pp. 141-156 (1993); Wallach,U.S. Pat. No. 4,911,928, assigned to Micro-Pak, Inc., issued Mar. 27,1990; and Weiner et al., U.S. Pat. No. 5,834,014, assigned to TheUniversity of Michigan and Micro-Pak, Inc., issued Nov. 10, 1998 (withrespect to Weiner et al., with a compound as described hereinadministered in lieu of, or in addition to, minoxidil).

The compounds of the present invention may also be administered byiontophoresis. See, e.g., internet sitewww.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banga et al.,“Hydrogel-based Iontotherapeutic Delivery Devices for TransdermalDelivery of Peptide/Protein Drugs”, Pharm. Res., Vol. 10 (5), pp.697-702 (1993); Ferry, “Theoretical Model of Iontophoresis Utilized inTransdermal Drug Delivery”, Pharmaceutical Acta Helvetiae, Vol 70, pp.279-287 (1995); Gangarosa et al., “Modern Iontophoresis for Local DrugDelivery”, Int. J. Pharm, Vol. 123, pp. 159-171 (1995); Green et al.,“Iontophoretic Delivery of a Series of Tripeptides Across the Skin invitro”, Pharm. Res., Vol 8, pp. 1121-1127 (1991); Jadoul et al.,“Quantification and Localization of Fentanyl and TRH Delivered byIontophoresis in the Skin”, Int. J. Pharm., Vol. 120, pp. 221-8 (1995);O'Brien et al., “An Updated Review of its Antiviral Activity,Pharmacokinetic Properties and Therapeutic Efficacy”, Drugs, Vol. 37,pp. 233-309 (1989); Parry et al., “Acyclovir Biovailability in HumanSkin”, J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992); Santi etal., “Drug Reservoir Composition and Transport of Salmon Calcitonin inTransdermal Iontophoresis”, Pharm. Res., Vol 14 (1), pp. 63-66 (1997);Santi et al., “Reverse Iontophoresis-Parameters DeterminingElectroosmotic Flow: I. pH and Ionic Strength”, J. Contuol. Release,Vol. 38, pp. 159-165 (1996); Santi et al., “ReverseIontophoresis—Parameters Determining Electroosmotic Flow: II. ElectrodeChamber Formulation”, J. Control. Release, Vol. 42, pp. 29-36 (1996);Rao et al., “Reverse Iontophoresis: Noninvasive Glucose Monitoring invivo in Humans”, Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995);Thysman et al., “Human Calcitonin Delivery in Rats by Iontophoresis”, J.Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994); and Volpato et al.,“Iontophoresis Enhances the Transport of Acyclovir through Nude MouseSkin by Electrorepulsion and Electroosmosis”, Pharm. Res., Vol. 12 (11),pp. 1623-1627 (1995).

The compositions used in the present invention may also optionallycomprise an activity enhancer. The activity enhancer can be chosen froma wide variety of molecules which can function in different ways toenhance hair growth effects of a compound of the present invention.Particular classes of activity enhancers include other hair growthstimulants and penetration enhancers.

Non-limiting examples of other hair growth stimulants which may be usedin the compositions herein, including both systemic and topicalcompositions, include, for example, benzalkonium chloride, benzethoniumchloride, phenol, estradiol, diphenhydramine hydrochloride,chlorpheniramine maleate, chlorophyllin derivatives, cholesterol,salicylic acid, cysteine, methionine, red pepper tincture, benzylnicotinate, D,L-menthol, peppermint oil, calcium pantothenate,panthenol, castor oil, hinokitiol, prednisolone, resorcinol,monosaccharides and esterified monosaccharides, chemical activators ofprotein kinase C enzymes, glycosaminoglycan chain cellular uptakeinhibitors, inhibitors of glycosidase activity, glycosaminoglycanaseinhibitors, esters of pyroglutamic acid, hexosaccharic acids or acylatedhexosaccharic acids, aryl-substituted ethylenes, N-acylated amino acids,and, of course, minoxidil or finasteride. The most preferred activityenhancers are minoxidil and finasteride, most preferably minoxidil.

Non-limiting examples of penetration enhancers which may be used in thecompositions herein include, for example, 2-methyl propan-2-ol,propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, POE(2) ethylether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, POE(2)methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid,propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propyleneglycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol,POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyladipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate,dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate,dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate,dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate,dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate,ethyl salicylate, iso-propyl palmitate, ethyl laurate, 2-ethyl-hexylpelargonate, iso-propyl isostearate, butyl laurate, benzyl benzoate,butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butylstearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hyroxyoctanoicacid, methylsulfoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide,2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides,sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,and, 1-dodecylazacyloheptan-2-one.

In all of the foregoing, of course, the compounds used in the presentmethods can be administered alone or as mixtures, and the compositionsmay further include additional drugs or excipients as appropriate forthe indication.

The present invention further relates to kits comprising a compoundand/or composition of the present invention and information and/orinstructions by words, pictures, and/or the like, that use of the kitwill provide treatment for hair loss in mammals (particularly humans)including, for example, arresting and/or reversing hair loss and/orpromoting hair growth. In addition or in the alternative, the kit maycomprise a compound and/or composition of the present invention andinformation and/or instructions regarding methods of application of thecompound and/or composition, preferably with the benefit of treatinghair loss in mammals.

EXAMPLES OF COMPOSITION ADMINISTRATION

The following examples do not limit the invention, but provide guidanceto the ordinarily skilled artisan to perform the methods of the presentinvention. In each example, a compound other than the one mentioned maybe substituted in the example by another having a structure as describedherein with similar results.

Example A

A composition for topical administration is made, comprising:

Component Amount Compound of Example 3  5% Ethanol 57% Propylene Glycol19% Dimethyl Isosorbide 19%

A human male subject suffering from male pattern baldness is treated bya method of this invention. Specifically, for 6 weeks, the abovecomposition is daily administered topically to the subject.

Example B

A composition for topical administration is made according to the methodof Dowton et al., “Influence of Liposomal Composition on TopicalDelivery of Encapsulated Cyclosporin A: I. An in vitro Study UsingHairless Mouse Skin”, S.T.P. Pharma Sciences, Vol. 3, pp. 404-407(1993), using the compound of Example 2 in lieu of cyclosporin A andusing the Novasome 1 for the non-ionic liposomal formulation.

A human male subject suffering from male pattern baldness is treatedeach day with the above composition. Specifically, for 6 weeks, theabove composition is administered topically to the subject.

Example C

A shampoo is made, comprising:

Component Ex. C-1 Ex. C-2 Ex. C-3 Ex. C-4 Ammonium Lauryl Sulfate 11.5% 11.5%  9.5% 7.5% Ammonium Laureth Sulfate   4%   3%   2%   2% CocamideMEA   2%   2%   2%   2% Ethylene Glycol Distearate   2%   2%   2%   2%Cetyl Alcohol   2%   2%   2%   2% Stearyl Alcohol 1.2% 1.2% 1.2% 1.2%Glycerin   1%   1%   1%   1% Polyquaternium 10 0.5% 0.25%  — —Polyquaternium 24 — — 0.5% 0.25%  Sodium Chloride 0.1% 0.1% 0.1% 0.1%Sucrose Polyesters of   3%   3% — — Cottonate Fatty Acid SucrosePolyesters of   2%   3% — — Behenate Fatty Acid Polydimethyl Siloxane ——   3%   2% Cocaminopropyl Betaine —   1%   3%   3% Lauryl DimethylAmine 1.5% 1.5% 1.5% 1.5% Oxide Decyl Polyglucose — —   1%   1% DMDMHydantoin 0.15%  0.15%  0.15%  0.15%  Compound of Example 1 —   3%   3%— Compound of Example 4   6% — —   6% Minoxidil   3%   2% Phenoxyethanol0.5% 0.5% 0.5% 0.5% Fragrance 0.5% 0.5% 0.5% 0.5% Water q.s. q.s. q.sq.s

A human subject suffering from male pattern baldness is treated by amethod of this invention. Specifically, for 12 weeks, the above shampoois used daily by the subject.

What is claimed is:
 1. A compound characterized by the structure:

and pharmaceutically acceptable salts, hydrates wherein: R₁, R₂, R₅, R₇,and R₁₀ are each, independently, selected from the group consisting ofhydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,and heteroalkynyl; R₄ is selected from the group consisting of halogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl;R₈ and R₉ are each, independently, selected from the group consisting ofhalogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl;R₃ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl,heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, heteroarylalkyl and heteroarylalkenyl; R₆ and R₆′ are each,independently, selected from the group consisting of nil and oxo; Y isbond; X is selected from the group consisting of —NZ— and —NH—; R₁₁ isselected from the group consisting of bond and —C(O)—; R₁₂ is selectedfrom the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, and heteroarylalkenyl; with the provisos that when R₁₁is bond, then R₁₂ and Z optionally are bonded together to form a cycleselected from the group consisting of a morpholine and a pyrrolidine;when R₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl,then a heteroatom of R₁₂ is not directly covalently bonded to R₁₁; whenR₁₂ is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl,then a heteroatom of R₁₂ is not directly covalently bonded to R₁₁; and Zis selected from the group consisting of alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, and heteroalkynyl; with the proviso thatwhen R₁₁ is bond, then R₁₂ and Z are optionally bonded together to forma cycle selected from the group consisting of a morpholine and apyrrolidine; wherein when R₁₂ is heteroalkyl, heteroalkenyl,heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R₁₂ is notdirectly covalently bonded to R₁₁.
 2. A compound according to claim 1wherein R₄, R₈, and R₉ are each, independently, selected from the groupconsisting of halogen, alkyl, alkenyl, and heteroalkyl; with the provisothat R₃ is selected from the group consisting of hydrogen, lower alkyl,and lower alkenyl.
 3. A compound according to claim 1 wherein R₆ and R₆′are each nil.
 4. A compound according to claim 3 wherein R₁₂ is selectedfrom alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl; with theproviso that when R₁₁ is bond, then R₁₂ and Z are optionally bondedtogether to form a cycle selected from the group consisting of amorpholine and a pyrrolidine.
 5. A compound according to claim 1 whereinR₁, R₂, R₅, R₇, and R₁₀ are each hydrogen.
 6. A composition comprising acompound of claim 1 and a carrier.
 7. A method of treating hair losscomprising administering to a mammal a composition according to claim 6.8. A method according to claim 7, wherein the administration is topical.